With the advance in genetic engineering, recently, development and studies on medicaments have been actively carried out, which use bio-related substances such as intercellular signaling substances such as hormones and cytokines, antibodies, and enzymes. Since these bio-related substances are usually cleared from the body because of the filtration through glomeruli in the kidney and the uptake by macrophages in the liver, spleen, and the like when the substances are injected to a living body, they have short half-lives in blood and hence it is difficult to obtain a sufficient pharmacological effect. For solving the problems, it is attempted to improve the behavior in a living body by encapsulating the bio-related substances in liposomes or polymer micelles or increasing their molecular weight or formation of a hydration layer through chemical modification with an amphiphatic polymer such as a sugar chain or polyethylene glycol or albumin. Moreover, by the modification with polyoxyalkylene, effects of decreasing toxicity and antigenicity and enhancing solubility of sparingly water-soluble pharmaceuticals are also obtained.
Recently, in the case of modifying a bio-related substance with polyoxyalkylene, in order not to block the active site or in order to obtain a larger hydration layer with lesser number of polyoxyalkylene, increase in molecular weight of a polyoxyalkylene derivative has been investigated. However, in the case of producing high-molecular-weight polyoxyalkylene, there arise problems in production, such as decrease in purity and increase in viscosity, and thus polyoxyalkylene suitable for a modifier of the bio-related substance is not efficiently obtained.
On the other hand, in order to perform more effective increase in molecular weight, development of the use of polyoxyethylene having a branched structure has been advanced. Patent Document 1 describes asparaginase using polyoxyalkylene having a double-chain structure containing cyanuric chloride as a main skeleton and Patent Document 2 describes interferon-α using polyoxyalkylene having a double-chain structure containing lysine as a main skeleton. Also, Patent Document 3 describes a bio-related substance using polyoxyalkylene having a double-chain structure containing 1,2-glycerol as a main skeleton.
These structures all have a double-chain structure as a basic skeleton but, in order to obtain a larger hydration layer, polyoxyalkylene having more highly branched structure has been required from the viewpoint of developing medical uses.
Patent Documents 4 and 5 describe polyoxyalkylene derivatives having tri- to penta-branched structure containing a cyclohexane ring, a monosaccharide such as glucose or sorbitol, or a polycarboxylic acid such as citric acid as a basic skeleton and Patent Documents 6 and 7 describe a polyoxyalkylene derivative having a quadruple-chain structure containing triglycerin as a basic skeleton.
Since the polyoxyalkylene derivatives described in Patent Documents 4 and 5 is produced by introduction to the basic skeleton such as a cyclic polyol by reacting an excess amount of a single-chain polyoxyalkylene derivative, excess single-chain polyoxyalkylene derivative not reacted with the basic skeleton remains and thus it should be removed. Moreover, when the number of the target polyoxyalkylene chains is a large number, since impurities wherein the target number of the chains has not been introduced are produced as by-products, it is very difficult to diminish these impurities and thus industrial production thereof is further difficult.
The polyoxyalkylene derivatives described in Patent Documents 6 and 7 are obtained by adding ethylene oxide to triglycerin monoallyl ether. However, in the case where an alkali is used as a catalyst for the addition reaction, the allyl ether is rearranged into a propenyl ether and, further in the case where an acid is used in a neutralization step or the like, the system becomes locally acidic and the propenyl ether is converted into a hydroxyl group, so that purity of the target product becomes low. Moreover, in Patent Documents 6 and 7, a carboxyl group or an amino group is introduced though formation of a sulfide bond by the reaction of the allyl ether group with a carboxylic acid having a mercapto group or an organic amine having a mercapto group, so that the obtained compounds are limited to only those having a sulfide bond.
As above, a derivative having a multiple number of polyoxyalkylene chains which is capable of being effectively used in use applications which involve modification of bio-related substances and is industrially easily produced has not been obtained and it is highly desired to develop such a multibranched polyalkylene derivative.
Patent Document 1: Japanese Patent Application Laid-Open: JP-B-61-42558
Patent Document 2: Japanese Patent Application Laid-Open: JP-A-10-67800
Patent Document 3: Japanese Patent Application Laid-Open: JP-A-2004-197077
Patent Document 4: WO01/048052 pamphlet
Patent Document 5: WO02/060978 pamphlet
Patent Document 6: Japanese Patent Application Laid-Open: JP-A-2000-1542
Patent Document 7: Japanese Patent Application Laid-Open: JP-A-2000-44674